Abstract

The genetic component of quantitative metabolic traits is complex with a mixture of common alleles of small effect and rarer alleles of larger effect. We have principally focused on finding the latter through the study of extreme human phenotypes of obesity and insulin resistance. By applying both candidate and hypothesis-free genetic approaches we have identified multiple different genetic variants that cause highly penetrant forms of these diseases. Through detailed phenotypic studies in humans and relevant murine and cellular models, these disorders continue to provide new insights into the physiology and pathphysiology of energy balance and metabolism. Of particular note is the discovery that highly penetrant alleles that cause human obesity do so largely by impairing satiety and increasing food intake, rather than my having effects on metabolic rate. Common alleles that influence susceptibility to common forms of obesity also behave in a similar fashion. Thus, obesity can be most appropriately viewed as a heritable neurobehavioral trait with adverse metabolic consequences rather than a metabolic disease per se. The dramatic therapeutic benefits of leptin in children with congenital leptin deficiency provides the proof of principle that, if an underlying mechanism can be identified, then even extreme human obesity can be amenable to mechanism-based therapy